Genome-wide association study of brain tau deposition as measured by 18F-flortaucipir positron emission tomography imaging.

The related genetic variants of tau deposition, a seminal pathological hallmark of Alzheimer's disease, remain poorly understood. We sought to perform a genome-wide association study of brain tau load as measured by AV1451 positron emission tomography (PET). Among 543 non-demented European individuals, novel associations with higher tau were identified for rs56298435 (p = 8.35 × 10-10, ß=0.31) within ZBTB20, and for rs150532 (p = 1.90 × 10-8, ß=0.26) in the protein phosphorylation regulatory gene EYA4. The APOE association additionally reached genome-wide significant when APOE ε4 was not adjusted. Minor allele carriers of rs56298435 or rs150532 showed higher levels of tau PET load. As expected, phosphorylated-tau analyses in both plasma and cerebrospinal fluid also revealed the same direction of effect. Functionally, the effects of novel loci on cognitive decline could be mediated by tau pathology. In addition, we observed that the expression of VNN2 as regulated by rs150532, together with EYA4, displayed significant correlations with the tau-related gene MAPT in numerous brain regions. Our novel finding lends additional credence to heritable underpinnings of tau deposition.

Associations of the Rate of Change in Geriatric Depression Scale with Amyloid and Cerebral Glucose Metabolism in Cognitively Normal Older Adults: A Longitudinal Study.

BACKGROUND: Depression is considered a psychological risk factor for Alzheimer's disease (AD). We sought to examine the differential associations of depression severity with cognitive decline, clinical progression to mild cognitive impairment (MCI) or AD, and neuroimaging markers of AD in cognitively normal older adults. METHODS: A total of 522 cognitively normal (CN) participants who underwent assessments for depression (longitudinal geriatric depression scale [GDS] ) and cognitive assessments were included from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. The cross-sectional and longitudinal associations of the rate of change in GDS with amyloid-ß (Aß)-positron emission tomography (PET), tau-PET, and 18F-fluorodeoxyglucose (FDG)-PET were explored. Kaplan-Meier survival curves of clinical progression and Aß accumulation were plotted based on mean annual changes in GDS. Mediation analyses were utilized to explore the mediation effects of AD markers. RESULTS: Higher rate of increase in GDS was associated with faster cognitive decline and higher risk of progression to MCI or AD. Moreover, the rate of change in GDS was significantly associated with Aß accumulation and cerebral glucose metabolism. The influences of the rate of change in GDS on cognition and clinical progression were partially mediated by Aß accumulation and cerebral glucose metabolism. LIMITATIONS: GDS is a self-reported questionnaire and not the same as a clinical diagnosis of depression. CONCLUSIONS: The cognitive and clinical consequences of changes in depressive symptoms partly stem from Aß accumulation and cerebral glucose metabolism, which increases our understanding of how depressive symptoms may increase vulnerability to dementia.